Sex Differences in Outcome of Aneurysmal Subarachnoid Hemorrhage and Its Relation to Postoperative Cerebral Ischemia.

BACKGROUND: Whether there is a sex difference in the outcome of aneurysmal subarachnoid hemorrhage (aSAH) remains controversial, and clarifying the role of women in postoperative cerebral ischemic events can help us to understand its relationship with poor prognosis. Therefore, the purpose of this study was to elucidate the relationship between the three aspects of sex differences, postoperative cerebral ischemia, and poor prognosis after aSAH. METHODS: A total of 472 patients admitted within 72 h after aSAH between January 2018 and December 2022 were included. We systematically analyzed the characteristics of sex differences in aSAH and explored the relationship between delayed cerebral ischemia (DCI), surgery-related cerebral infarction (SRCI), and poor prognosis (modified Rankin Scale > 2). RESULTS: Compared with women, men were in worse condition and had more intracerebral hematoma (p = 0.001) on admission, whereas women were older (p < 0.001) and had more multiple aneurysms (p = 0.002). During hospitalization, men were more likely to experience emergency intubation (p = 0.036) and tracheotomy (p = 0.013). Women achieved functional independence at discharge at a similar rate to men (p = 0.394). Among postoperative complications, the incidence of DCI (22% vs. 12%, p = 0.01) and urinary tract infection (p = 0.022) was significantly higher in women. After adjusting for age, multivariable regression analysis showed that hypertension (odds ratio [OR] 2.139, 95% confidence interval [CI] 1.027-4.457), preoperative rerupture (OR 12.240, 95% CI 1.491-100.458), pulmonary infection (OR 2.297, 95% CI 1.070-4.930), external ventricular drainage placement (OR 4.382, 95% CI 1.550-12.390), bacteremia (OR 14.943, 95% CI 1.412-158.117), SRCI (OR 8.588, 95% CI 4.092-18.023), venous thrombosis (OR 5.283, 95% CI 1.859-15.013), higher modified Fisher grades (p = 0.003), and Hunt-Hess grades (p = 0.035) were associated with poor prognosis, whereas DCI (OR 1.394, 95% CI 0.591-3.292) was not an independent risk factor for poor prognosis. The proportion of patients who fully recovered from cerebral ischemia was higher in the DCI group (p < 0.001) compared with the SRCI group, and more patients were discharged with modified Rankin Scale > 2 in the SRCI group (p = 0.005). CONCLUSIONS: Women have a higher incidence of DCI, but there is no sex difference in outcomes after aSAH, and poor prognosis is associated with worse admission condition and perioperative complications. SRCI is a strong independent risk factor for poor prognosis, whereas DCI is not.

Perioperative complications of arteriovenous tirofiban administration versus oral dual antiplatelet therapy for stent-assisted embolization treated aneurysmal subarachnoid hemorrhage: A retrospective, controlled cohort analysis.

BACKGROUND: Major perioperative complications of stent-assisted embolization treated for aneurysmal subarachnoid hemorrhage patients include the formation of thromboembolic events (TEs) and hemorrhagic events (HEs), for which antiplatelet protocols play a key role. METHODS: We conducted a single-center retrospective analysis to compare the differences between arteriovenous tirofiban administration with traditional oral dual antiplatelet therapy (DAPT). A total of 417 consecutive patients were enrolled. General clinical characteristics, as well as the perioperative ischemic and hemorrhagic events, were retracted in digital documents. Logistic regression was conducted to identify both risk and protective factors of perioperative TEs and HEs. RESULTS: Perioperative TEs occurred in 21 patients, with an overall perioperative TEs rate of approximately 5.04%; among these patients, the incidence of perioperative TEs in the tirofiban group was less than that in the DAPT group. Additionally, 66 patients developed perioperative HEs, with an incidence of approximately 15.83%; among these patients, the incidence of perioperative HEs was less than that in the DAPT group. No significant differences were seen between the two groups in terms of the mRS score at the time of discharge. CONCLUSION: This study indicated that an improved perioperative antiplatelet drug tirofiban was an independent protective factor for perioperative TEs in stent-assisted embolization of ruptured intracranial aneurysms, but it did not impart an elevated risk of perioperative HEs and had no significant effects on the near-term prognosis of the patients.

C3/C3aR inhibition alleviates GMH-IVH-induced hydrocephalus by preventing microglia-astrocyte interactions in neonatal rats.

Activation of microglia and astrocytes following germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) plays a detrimental role in posthemorrhagic hydrocephalus (PHH). It is still unclear whether or how an interaction occurs between microglia and astrocytes in PHH. Here, we investigated the role of the C3/C3aR pathway in microglia and astrocyte interactions and whether C3/C3aR-targeted inhibition could alleviate PHH following GMH-IVH. A total of 152 Sprague-Dawley rats at postnatal day seven (P7) were enrolled in the study, and collagenase VII was used to induce GMH-IVH. Minocycline (45 mg/kg) was administered to inhibit microglial activation. Complement C3a peptide and C3aR antagonist (SB 290157, 10 mg/kg) were used to regulate the C3/C3aR pathway. As a result, the data demonstrated that periventricular C3aR+/Iba-1+ microglia and C3+/GFAP+ astrocytes were significantly increased in GMH-IVH pups at 28 days after surgery. Intranasal C3a peptide upregulated C3aR expression in microglia. Inhibition of microglia by minocycline decreased both C3+/GFAP+ astrocytes and the colocalization volume of Iba-1 and GFAP. In addition, intraperitoneally injected C3aRA alleviated the periventricular colocalization volume of microglia and astrocytes. Compared with vehicle-treated pups, the protein level of IL-1ß, IL-6 and TNF-α in cerebral spinal fluid and brain tissue at 28 days following GMH-IVH were reduced in C3aRA-treated pups. Moreover, hydrocephalus was alleviated, and long-term cognitive ability were improved in the C3aRA-treated group. Our data presented simultaneous periventricular astrogliosis and microgliosis of pups following GMH-IVH and proved their potential interaction through the C3/C3aR pathway, indicating C3aRA as a potential pharmacological treatment of PHH in neonates.

[A Comparative Study of Intraoperative Application of Fluorescein and Indocyanine Green Videoangiography in Intracranial Aneurysm Clipping Surgery].

OBJECTIVE: To compare the application of fluorescein videoangiography (FL-VA) and indocyanine green videoangiography (ICG-VA) in intracranial aneurysm surgery. METHODS: A total of 65 patients who underwent aneurysm clipping in our hospital from January 2019 to January 2020 were included in the study. FL-VA and ICG-VA were used during the surgery to determine whether the aneurysm is completely clipped and the artery bearing the aneurysm and the perforating artery around the aneurysm are unobstructed. RESULTS: All 65 patients underwent both FL-VA and ICG-VA intraoperatively after aneurysm clipping. FL-VA was applied first. In 30 cases, FL-VA and ICG-VA provided the same results. In 10 cases, FL-VA performed obviously better over ICG-VA in visualizing small perforating arteries (2 cases of internal carotid artery-posterior communicating artery aneurysms and 3 cases of anterior communicating artery aneurysm) and evaluating whether the aneurysm was completely clipped (3 cases of middle cerebral artery aneurysm, 1 case of internal carotid artery-posterior communicating artery aneurysms and 1 case of distal anterior cerebral artery aneurysm). In the remaining 25 cases, ICG-VA was repeatedly applied in a short period of time due to quick clearance of indocyanine green from the blood vessels, but this couldn't be done with FL-VA. CONCLUSIONS: Compared with ICG-VA, FL-VA can provide better visualization of perforating artery, and can determine whether the aneurysm was completely clipped more accurately. However FL-VA couldn't be repeatedly applied during a short period of time.

Treatment of traumatic intracranial aneurysm: Experiences at a single center.

OBJECTIVE: To report the treatment and outcome of traumatic intracranial aneurysm (TICA) cases at the Southwest Hospital, Army Medical University in China. PATIENTS AND METHODS: All patients diagnosed with TICA at our institution from January 1, 1977, to October 31, 2018, and meeting the inclusion/exclusion criteria were included in the study. Cases were reported separately for those diagnosed before 1998 and those after 1998. RESULTS: A total of 25 patients were included in the study. Ten were diagnosed with TICA prior to 1998. Seven of these 10 patients were treated surgically with parent artery sacrificed, including aneurysmectomy, trapping, and bypass. The mean Glasgow Outcome Scale (GOS) score for the 7 patients with surgical treatment was 3.1. Three of the 10 patients died of severe complications, including intracranial infection, delayed bleeding, and deadly injury. After 1998, 15 patients were diagnosed with TICA. Thirteen presented with head trauma and two with iatrogenic TICA following ventricle drainage or sphenoid ridge meningioma resection. Thirteen were treated with endovascular treatment, including coil alone, glue, coil-associated glue, stent alone, stent-assisted coil embolization, one with clipping, and one with conservative treatment. The 13 patients with endovascular treatment achieved a mean GOS score of 4.5. Among the 13 patients, one died from intracranial infection, one suffered recurrence, and one had intraoperative rupture. CONCLUSION: Although the treatment of TICA has traditionally been surgical, endovascular treatment with different techniques, such as endovascular patch, provides a valuable alternative. Currently, the flow diverter is a popular embolization device and may represent another valid treatment option for TICA.

Edaravone Administration Confers Neuroprotection after Experimental Intracerebral Hemorrhage in Rats via NLRP3 Suppression.

OBJECTIVES: Intracerebral hemorrhage (ICH) is one of the leading causes of disability and mortality in adult, which lacks effective therapies. Edaravone has showed its neuroprotective effects after ischemia stroke, but its effects and possible mechanisms after ICH are poorly understood. Here, we investigated whether edaravone confers neuroprotection after ICH in rats and explored the potential mechanisms involved. METHODS: ICH was induced in the right basal ganglia of Sprague-Dawley rats by stereotacticly injection of 200 µl autologous blood. Edaravone (3 mg/kg) or vehicle (saline) was administered intravenously and NLRP3 selective antagonist (MCC950, 10 mg/kg) was intraperitoneally injected to study the potential mechanism. Water Morris Maze Test and Rotarod test were used to elucidate neurological function and Fluoro-Jade C was used to study neurodegeneration after ICH. Western blot assay, Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry were used to check the expression of molecules involved. RESULTS: As a result, we found that edaravone significantly alleviated brain edema and conferred the neurological deficits of rats after ICH. Hematoma increased NLRP3 expression in microglia, which was decreased by edaravone. Moreover, we demonstrated that edaravone shared a similar effect with MCC950 on alleviating neurodegeneration and decreasing the expression of IL-1ß, Caspase 1 and NF-κB in protein or mRNA. Lastly, edaravone and MCC950 both increased the number of Tuj-1 positive neuronal cells peripheral hematoma. CONCLUSIONS: The present study demonstrated that edaravone conducted neuroprotection after ICH partially via suppressing NF-κB-dependent NLRP3 in microglia, which contributed a novel evidence for clinic usage of edaravone after ICH.

NF-κB potentiates tumor growth by suppressing a novel target LPTS.

BACKGROUND: Chronic inflammation is causally linked to the carcinogenesis and progression of most solid tumors. LPTS is a well-identified tumor suppressor by inhibiting telomerase activity and cancer cell growth. However, whether and how LPTS is regulated by inflammation signaling is still incompletely elucidated. METHODS: Real-time PCR and western blotting were used to determine the expression of p65 and LPTS. Reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation were performed to decipher the regulatory mechanism between p65 and LPTS. Cell counting kit-8 assays and xenograt models were used to detect p65-LPTS-regulated cancer cell growth in vitro and in vivo, respectively. RESULTS: Here we for the first time demonstrated that NF-κB could inhibit LPTS expression in the mRNA and protein levels in multiple cancer cells (e.g. cervical cancer and colon cancer cells). Mechanistically, NF-κB p65 could bind to two consensus response elements locating at -1143/-1136 and -888/-881 in the promoter region of human LPTS gene according to EMSA and ChIP assays. Mutation of those two binding sites rescued p65-suppressed LPTS promoter activity. Functionally, NF-κB regulated LPTS-dependent cell growth of cervical and colon cancers in vitro and in xenograft models. In translation studies, we verified that increased p65 expression was associated with decreased LPTS level in multiple solid cancers. CONCLUSIONS: Taken together, we revealed that NF-κB p65 potentiated tumor growth via suppressing a novel target LPTS. Modulation of NF-κB-LPTS axis represented a potential strategy for treatment of those inflammation-associated malignancies.

A selective CB2R agonist (JWH133) restores neuronal circuit after Germinal Matrix Hemorrhage in the preterm via CX3CR1+ microglia.

Microglia play dual roles after germinal matrix hemorrhage, and the neurotrophic phenotype maybe neuroprotective. However, the phenotype transformation and the way by which neuron-microglia dialogue remain unclear. We raise the hypothesis that a cannabinoid receptor2 agonist (JWH133) accelerates the CX3CR1+ microglia secreting neurotrophic factors and restores damaged neuronal circuit. Here, we report a novel function of JWH133 in transforming the microglia CX3CR1 positive that secrete brain-derived neurotrophic factor (BDNF), which triggers neuron proliferation and neuronal restoration. Using a collagen VII-induced GMH model in rat pups postnatal day 7 (P7), we found that the drug showed robust activity in neuronal precursors. Moreover, the FA value of DTI in the internal zone revealed the positive effects of JWH133 on neural restoration. CX3CR1, a critical modulating molecule expressed in microglia, was upregulated after treatment with JWH133 and the corresponding shRNA (NM_133534.1) was used to silence the expression of CX3CR1. 3 days after treatment with JWH133, we detected reduced expression of biomarkers for neural progenitor cells (NPCs) in pups pre-injected in the lateral ventricular tissue with CX3CR1 shRNA, but not in pups injected with control shRNA. Overall, this study provides evidence that JWH133 promoted a neurotrophic phenotype of microglia (CX3CR1+ microglia), beyond merely alleviating microglial proliferation and inflammation. Moreover, JWH133 restored impaired neuronal circuit, which represent a novel therapeutic strategy following GMH in clinic.

Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2.

Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes.

Acute visual loss in an orbital arteriovenous malformation.

Arteriovenous malformations (AVMs) of the orbit are rare and are thought to be congenital. They can grow slowly or in a delayed fashion after a prolonged period of quiescence if there is a hemodynamic balance between the in-flow and the out-flow vessels. However, once the balance is destroyed, orbital AVMs may cause acute visual deterioration. We report a 17-year-old male with orbital AVM, and discuss the mechanism and the management of acute visual deterioration in this setting. Angiography revealed an orbital AVM with obvious drainage obstruction and serious orbital congestion, due to the disruption of the balance. He had no vision improvement although treated successfully with radical transarterial embolization. The worsening of drainage obstruction could alter the hemodynamic flow and lead to acute visual deterioration. Early and exact diagnosis and complete transarterial embolization therapy are important before the hemodynamic imbalance.

An early successful surgical treatment of fibrinolysis-related symptomatic intracerebral hemorrhage without procoagulant therapy.

Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is clinically effective at treating acute ischemic stroke. However, the use of thrombolytic therapy is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH). Whether unacceptable surgical hemorrhage occurs after emergent decompressive craniotomy during the first hours for sICH remains unknown. We report a 69-year-old Chinese woman with a fibrinolysis-related sICH, and discuss the efficacy and the safety of craniotomy in this setting. An urgent decompressive craniotomy was performed through a standard pterional approach without any procoagulant therapy before operation. No unacceptable surgical hemorrhage occurred during the first hours after onset of sICH, and the outcome of this patient is fairly good. Early urgent decompressive craniectomy in the treatment of fibrinolysis-related sICH may be a safe therapy, which may improve clinical outcomes.